1. Field of the Invention
The present invention relates generally to the fields of developmental biology and molecular biology. More particularly, it concerns gene regulation and cellular physiology in cardiomyocytes.
2. Description of Related Art
Cardiac cells do not divide after birth, so both normal growth of the myocardium as well as stress-induced myocardial remodeling must take place through hypertrophic growth without cell division (MacLellan and Schneider, 2000). Cardiac hypertrophy can occur by an increase in width of myofibrils, resulting in a thickening of the myocardial wall or “concentric hypertrophy,” or by an increase in myofibril length, producing chamber dilation or “eccentric hypertrophy.” These contrasting forms of hypertrophy are coupled to parallel versus serial assembly of sarcomeres, respectively.
In the case of normal physiological growth or exercise-induced hypertrophy, concentric and eccentric hypertrophy occur simultaneously and in a balanced manner, enabling the heart to increase pumping capacity in response to increased demand. Disease states that put stress on the heart can also induce hypertrophy. Depending on the stimulus, however, either concentric or eccentric hypertrophy may predominate. Although hypertrophy may initially compensate for the additional demands placed on the heart by disease, almost inevitably continued stress results in decompensation and the development of hypertrophic or dilated cardiomyopathy. In order for any form of hypertrophic remodeling to occur, stress stimuli must activate signaling pathways that regulate protein synthesis, sarcomeric assembly and organization, and gene expression (Chien, 1999; Nicol et al., 2000; Sugden and Clerk, 1998).
Mitogen-activated protein kinase (MAPK) pathways provide an important connection between external stimuli that activate a wide variety of cell-signaling systems and the nucleus. At the core of each MAPK cascade is a three-kinase module in which the most downstream member, the MAPK, is activated by a MAPK kinase (MAPKK or MEK), which is in turn activated by a MAPKK kinase (MAPKKK or MEKK) (English et al., 1999a). MAPKs can be divided into three major subfamilies based on sequence homology: the extracellularly-responsive kinases (ERKs), the c-Jun NH2-terminal kinases (JNKs), also known as stress-activated protein kinases (SAPKs), and the p38-MAPKs. In the heart, all three classes of MAP kinases are activated by G-protein coupled receptor (GPCR) agonists, stretch, and certain types of stress, including ischemia (Abe et al., 2000; Ruwhof and van der Laarse, 2000; Sugden and Clerk, 1998). A critical role for MAPK pathways in the development of hypertrophy in vivo has been demonstrated by the finding that transgenic expression of a MAP kinase phosphatase in the mouse heart can attenuate hypertrophy induced by aortic banding and catecholamine infusion (Bueno et al., 2001). The role of individual MAPK pathways in various aspects of the hypertrophic response is more controversial (Sugden and Clerk, 1998).
ERK5, also known as big MAPK 1 (BMK1), has an amino terminal domain that is homologous to ERKs 1 and 2, but has unique carboxyl-terminal and loop-12 domains (Lee et al., 1995; Zhou et al., 1995). MEK5, the activating MAPKK for ERK5, is a highly specific ERK5 kinase and does not activate other MAPKs even when overexpressed in cultured cells (English et al., 1995; Zhou et al., 1995). MEK5-ERK5 signaling has been shown to be activated by growth stimuli including serum and ligands for tyrosine kinase and GPCRs (Fukuhara et al., 2000; Kamakura et al., 1999; Kato et al., 1997), as well as by oxidative and osmotic stress (Abe et al., 1996). Signaling by this MAPK module has not been studied in detail in cardiac cells, but one report suggests that ERK5 may be regulated differently from ERK1/2 in these cells (Takeishi et al., 1999). Interestingly, the MEK1 inhibitors PD098059 and U0126 also inhibit activation of ERK5 (Kamakura et al., 1999), suggesting that functions previously attributed to ERK1/2 may also be mediated by ERK5.